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US20030225047A1 - Sulfatase inhibiting progestogen-only contraceptive regimens - Google Patents

Sulfatase inhibiting progestogen-only contraceptive regimens Download PDF

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Publication number
US20030225047A1
US20030225047A1 US10/385,867 US38586703A US2003225047A1 US 20030225047 A1 US20030225047 A1 US 20030225047A1 US 38586703 A US38586703 A US 38586703A US 2003225047 A1 US2003225047 A1 US 2003225047A1
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Prior art keywords
cycle
progestogen
administration
contraceptive
estrogen
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US10/385,867
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English (en)
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Patrick Caubel
Andrew Friedman
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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Priority to US10/385,867 priority Critical patent/US20030225047A1/en
Assigned to JANSSEN PHARMACEUTICA N.V. reassignment JANSSEN PHARMACEUTICA N.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRIEDMAN, ANDREW JOSEPH, CAUBEL, PATRICK MICHAEL
Publication of US20030225047A1 publication Critical patent/US20030225047A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Definitions

  • the present invention relates to progestogen-only contraceptive regimens for menstruating females. More particularly, the present invention relates to progestogen-only contraceptive regimens containing a potent sulfatase inhibiting progestogen, such as, norgestimate (NGM) or norelgestromin (NGMN).
  • a potent sulfatase inhibiting progestogen such as, norgestimate (NGM) or norelgestromin (NGMN).
  • FIG. 1 shows the enzymatic process by which estrogens are locally formed in human breast cancer cells and thereby made available to support growth. (see ref #10 at 229). Referring to FIG. 1, studies have shown that the sulfatase enzyme appears to be at least 10 ⁇ more important in the formation of estrogens than the aromatase enzyme.
  • estradiol is one of the main factors involved in supporting growth of hormone-dependent breast tumours and the sulfatase pathway is the main pathway for the formation of estradiol in the breast, then a decrease of estradiol formation by suppression of the sulfatase pathway would have potential therapeutic activity in the management of breast cancer. (see refs #1 at 493, #3 at 55, #4 at 17, #5 at 931, #6 at 123 and #11 at 631) Suppression of the sulfatase pathway will have a breast protective effect.
  • a method of contraception comprising the step of administering to a menstruating female a cycle of contraceptive therapy, said cycle of therapy including the continuous administration for the length of the cycle of a potent sulfatase inhibiting progestogen in a contraceptively effective and breast protecting dose, in the absence of the administration of an estrogen.
  • a contraceptive therapy unit for administration to a menstruationg female comprising a cycle of separate dosage units adapted for successive daily oral administration for the length of the cycle, wherein said dosage units contain, in admixture with a pharmaceutically acceptable carrier, a potent sulfatase inhibiting progestogen in a contraceptively effective and breast protecting dose, in the absence of an estrogen.
  • a contraceptive therapy unit for administration to a menstruationg female comprising a cycle of transdermal patches adapted for successive administration for the length of the cycle, wherein said transdermal patches contain, in a suitable matrix, a potent sulfatase inhibiting progestogen in a contraceptively effective and breast protecting dose, in the absence of an estrogen.
  • a contraceptive therapy unit for administration to a menstruationg female comprising a cycle of vaginal rings adapted for successive administration for the length of the cycle, wherein the vaginal rings contain, in a suitable matrix, a potent sulfatase inhibiting progestogen in a contraceptively effective and breast protecting dose, in the absence of an estrogen.
  • FIG. 1- Shows the enzymatic process involved in the formation and transformation of estrogens in human breast cancers.
  • the contraceptive regimen according to the present invention is a progestin-only contraceptive regimen in which a progestogen is continuously administered in a sufficient dose to have a contraceptive effect and the regimen is administered cycle after cycle to a menstruating female to achieve a long term contraceptive effect.
  • no estrogen is administered and there is no period of time without hormone administration to allow for menstruation.
  • Menstruating female is intended to refer to fertile women of child-bearing age.
  • the method of administration might be transdermal, vaginal or oral. Where administration is transdermal, a suitable patch is continuously worn with replacement as required. Where administration is vaginal, a suitable vaginal device, such as a ring, is continuously inserted with replacement as required. Where administration is oral, daily oral dosage units are administered.
  • the cycle of administration usually lasts 28 days or more, but it may be longer up to 60 and even 90 days or shorter down to 21 days.
  • the cycle may include a regimen in which there is a day to day or week to week variation in the dose of progestogen administered according to a set pattern. In such a case the regimen, including variation of dose, is repeated in cycle following cycle.
  • the cycle may also be a regimen in which there is no variation in the dose of the active administered. In such a case, the cycle is nothing more than a convention representing a convenient unit of administration or sale. In either case, a contraceptive product utilizing the contraceptive regimen in question is prescribed, sold and administered in units of cycles.
  • the contraceptive product based on a cycle might be 1 to 10 of vaginal rings that are inserted and then replaced every 7, 14 or 21 days according to their design.
  • the contraceptive product based on a cycle might be 2 to 10 transdermal patches that are attached and then replaced every 7, 10 or 14 days according to their design.
  • the contraceptive product based on a cycle might be 21, 28, 56 or more tablets that are orally administered daily.
  • Progestogen herein is intended to refer to a progestin receptor modulator having a progestogenic effect.
  • a potent sulfatase inhibiting progestogen is preferably herein defined as a progestogen which has (or a progestogen with a substantial metabolite thereof which has) an IC 50 in the conversion of E 1 S to E 2 in either the MCF-7 or T-47D breast cancer cell lines of about the corresponding IC 50 of norelgestromin or lower.
  • a potent sulfatase inhibiting progestogen may also be a progestogen which has (or a progestogen with a substantial metabolite thereof which has) an IC 50 in the conversion of E 1 S to E 2 in either the MCF-7 or T-47D breast cancer cell lines of substantially less than the corresponding IC 50 of medroxyprogesterone acetate, for example, on the order of 1 ⁇ 3, 1 ⁇ 2 or 1 ⁇ 5 of the IC 50 of medroxyprogesterone acetate.
  • a potent sulfatase inhibiting progestogen can also be defined as a progestogen having (or a progestogen with a substantial metabolite thereof which has) an IC 50 in the conversion of E 1 S to E 2 in either the MCF-7 or T-47D breast cancer cell lines of at most about ⁇ fraction (1/10) ⁇ , or about preferably ⁇ fraction (1/100) ⁇ , the corresponding IC 50 of medroxyprogesterone acetate (MPA).
  • MPA medroxyprogesterone acetate
  • a potent sulfatase inhibiting progestogen can also be defined as a progestogen which inhibits (or a progestogen with a substantial metabolite thereof which inhibits) at least about 70% and preferably at least about 90% of the conversion of E 1 S to E 2 in either the MCF-7 or T-47D breast cancer cell lines where employed in the test at a concentration of 50 ⁇ 10 ⁇ 6 mol/l.
  • Norgestimate or norelgestromin (NGMN) are the preferred progestogens utilized herein and are each known to the art of contraceptive therapy.
  • norgestimate is now used in a number of commercially available contraceptive products.
  • the most preferred progestogen is norelgestromin (17-d-norgestimate).
  • Norelgestromin is the major metabolite of norgestimate in humans with 80% and higher of norgestimate being converted to norelgestromin in vivo. For this reason, inhibition of sulfatase enzyme activity which is demonstrated for norelgestromin is inferred to norgestimate.
  • the progestogen is administered in an amount sufficient to produce a contraceptive effect. According to the present invention, it is now an additional requirement that the progestogen be administered in an amount which is an effective breast protective amount. More specifically, in a first characterization of a breast protective and otherwise suitable amount of progestogen, there is administered sufficient sulfatase inhibiting progestogen such that it is at least equivalent in both contraceptive and breast protecting effect to about 0.030 mg to about 0.750 mg of orally administered norgestimate. Preferably, there is administered sufficient sulfatase inhibiting progestogen such that it is at least equivalent in both contraceptive and breast protecting effect to about 0.050 mg to about 0.300 mg of orally administered norgestimate.
  • a breast protective amount of progestogen in another characterization of a breast protective amount of progestogen and assuming a contraceptively effective amount, there is administered sufficient active compound to provide for, during a substantial portion of each day, a substantial suppression of sulfatase activity, for example, of 50% or greater and preferably of 67% or greater and most preferably of 75% or greater.
  • a substantial portion of a day is intended to mean a period of at least 4 hours, but within the invention might mean a period of at least 8 hours or 12 hours or even 24 hours.
  • norgestimate or norelgestromin in the case of a daily oral tablet, there is administered a preferred dose of norgestimate or norelgestromin (or an equivalent amount of a suitable progestogen to achieve the desired contraceptive and enzyme suppressive effect) between about 30 mcg to about 500 mcg and more preferably between about 150 mcg to about 300 mcg.
  • Specific daily oral tablets might contain 100, 125, 180, 215 or 250 mcg of norgestimate or norelgestromin.
  • a preferred ring delivers to systemic circulation a daily dose of norgestimate or norelgestromin (or an equivalent amount of a suitable progestogen to achieve the desired contraceptive and enzyme suppressive effect) between about 20 mcg to about 300 mcg and more preferably between about 90 mcg to about 200 mcg.
  • a specific vaginal ring might be inserted for one week and deliver to systemic circulation in that period of time an average daily dose of 60, 75, 100, 125 or 150 mcg of norgestimate or norelgestromin.
  • a preferred patch delivers to systemic circulation a daily dose of norgestimate or norelgestromin (or an equivalent amount of a suitable progestogen to achieve the desired contraceptive and enzyme suppressive effect) between about 20 mcg to about 300 mcg and more preferably between about 90 mcg to about 200 mcg.
  • a specific patch might be worn for one week and deliver to systemic circulation in that period of time an average daily dose of 60, 75, 100, 125 or 150 mcg of norgestimate or norelgestromin.
  • the progestogen is orally administered in tablets also containing a pharmaceutically acceptable non-toxic carrier.
  • suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, methylcellulose, sodium carboxylmethylcellulose, and the like.
  • the tablet may also contain one or more substances, which act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents as well as encapsulating materials.
  • the active agents are processed, together with the usual additives, vehicles and/or flavor-ameliorating agents normally employed in Galenic pharmacy, in accordance with generally accepted pharmaceutical practices.
  • the hormone containing tablets might also contain nutritional supplements such as, for example, iron supplements, folic acid, calcium, vitamin B 6 , vitamin B 12 , etc.
  • nutritional supplements such as, for example, iron supplements, folic acid, calcium, vitamin B 6 , vitamin B 12 , etc.
  • the active agents are granulated with spray dried lactose, a lubricating agent and a colorant and compressed.
  • Oral tablets are preferably packaged in the form of a pharmaceutical kit or package in which the daily dosages are arranged for proper sequential administration.
  • This invention also relates, therefore, to a pharmaceutical unit which contains the tablets of the regimen in a synchronized, fixed sequence, wherein the sequence or arrangement of the dosage units corresponds to the regimen of daily administration.
  • the progestogen may be transdermally administered by use of a patch.
  • patches are devices that contain at a minimum a drug reservoir matrix for holding the drug and metering the drug deposition or delivery to the skin, a backing, and an adhesive layer for adhering the device to the patient.
  • the device may contain other layers such as a drug release rate controlling layer for modulating delivery rate, and the like.
  • the device may contain permeation enhancers to increase the rate of penetration of drugs across the skin.
  • Patches are well known and understood by persons skilled in the art. Patches are now employed in marketed products for the administration of certain progestogen. Specific patches and even their application to steroids of the type described herein are described in U.S. Pat. Nos. 5,474,783; 5,656,286; 5,958,446; 6,024,976; 5,252,334; 5,006,342; and 4,906,463.
  • the progestogen may be intravaginally administered, preferably together, by use of a ring.
  • rings are devices having an elastomeric portion or body into which the active steroid is dispersed and which acts as a reservoir and meter for the diffusion of active to the lining of the vagina.
  • the ring may be composed entirely of elastomer with steroid homogenously dispersed throughout as described in U.S. Pat. No. 3,545,397.
  • the ring may have an inert inner core surrounded by an active containing elastomeric layer as described in U.S. Pat. No. 4,012,496.
  • the ring may have an elastomeric active containing inner core surrounded by a thin elastomeric layer initially containing no active.
  • the ring may have an inert core, surrounded by an active containing elastomeric layer and further surrounded by an elastomeric outer layer of variable thickness initially containing no active as described in U.S. Pat. No. 4,292,965.
  • the elastomer, the layered design of the ring, its surface area, the concentration of active, the nature of the active, etc. all combine to determine the release rate of active. Rings are well known and understood by persons skilled in the art. Rings are now employed in marketed products for the administration of certain steroids. Further specific rings and their application to steroids of the type described herein are described in U.S. Pat. Nos. 4,871,543 and 5,188,835.
  • [0048] [6,7- 3 H(N)]-estrone sulfate ( 3 H-E 1 S), ammonium salt (sp. act. 53 Ci/mmol) and [4- 14 C]-estradiol ( 14 C-E 2 ) (sp. act. 57 mCi/mmol) were purchased from New England Nuclear Division (DuPont de Nemours, Les Ulls, France). The purity of the radioisotopes was assessed by thin-layer chromatography (TLC) in the appropriate system before use.
  • E 1 S, ammonium salt, unlabeled E 1 and E 2 , (analytical grade) were obtained from Sigma-Aldrich Chimle, (St Quentin Fallavier, France).
  • the hormone-dependent MCF-7 and T-47D human mammary cancer cell lines were grown in Eagle's Minimal Essential Medium (MEM) buffered with 10 mmol/l HEPES (pH 7.6), supplemented with 2 mmol/l L-glutamine, 100 U/ml penicillin-streptomycin and 5% fetal calf serum (FCS) (A.T.G.C., Marne-la-Vhui, France) for T-47D, or 10% FCS for MCF-7 cells, and incubated at 37° C. n a humidified atmosphere of 5% CO 2 . Media were changed twice a week.
  • MEM Eagle's Minimal Essential Medium
  • HEPES pH 7.6
  • FCS fetal calf serum
  • the cells were passed every 10-12 days and replated in 75 cm 2 flasks (A.T.G.C.) at 3 ⁇ 10 6 cells/flask. Four days before the experiments, the cells were transferred to MEM containing 5% steroid-depleted treated FCS. The FCS had been treated overnight at 4° C. with dextran-coated charcoal (DCC)(0.1-1% w/v, DCC-FCS).
  • DCC dextran-coated charcoal
  • MCF-7 and T-47D cell lines used herein were deposited in accordance with the Budapest Treaty under the references MCF7_JJPRD and T47D_JJPRD on May 17, 2002 at The Belgian Co-ordinated Collections of Micro-organisms (BCCM), Laboratorium voor Mole Les Biologie, Universiteit Gent, K. L. Ledeganckstraat 35, B-9000 Gent, Belgium and are publicly available under accession numbers LMBP 5862CB and LMBP 5863CB, respectively.
  • Preconfluent cells were incubated for 4 hours at 37° C. in MEM-DCC-FCS with the addition of 5 ⁇ 10 ⁇ 9 mol/l of [ 3 H]-E 1 S, alone (control cells) or in combination with the different compounds: NGMN or MPA, dissolved in ethanol (final concentration ⁇ 0.2%), at a range of concentrations of 5 ⁇ 10 ⁇ 5 -5 ⁇ 10 ⁇ 9 mol/l.
  • Control cells received ethanol vehicle only. After 24 hours, the medium was removed, the cells washed twice with ice-cold Hank's Buffered Saline Solution (HBSS, calcium-magnesium-free)(A.T.G.C.) and harvested by scraping.
  • HBSS Hank's Buffered Saline Solution
  • Table 3 shows the effects of NGMN and medroxyprogesterone acetate (MPA) concentrations on the conversion of E 1 S to E 2 in the hormone-dependent human breast cancer cell line T-47D
  • the data are the mean ⁇ SEM of duplicate determinations of 3 independent experiments.
  • E 2 formed fmol/mg DNA mol/l (% inhibition) (% inhibition) 0 (control) 1805 ⁇ 152 (0%) 0.005 1029 ⁇ ?
  • Table 4 shows the effects of NGMN and medroxyprogesterone acetate (MPA) concentrations on the conversion of E 1 S to E 2 in the hormone-dependent human breast cancer cell line MCF-7.
  • the data are the mean ⁇ SEM of duplicate determinations of 3 independent experiments.
  • Table 5 shows the IC 50 values for NGMN and medroxyprogesterone acetate (MPA) in the conversion of E 1 S to E 2 in the hormone-dependent human breast cancer cell lines MCF-7 and T-47D.
  • IC 50 values correspond to the 50% inhibition of the conversion of E 1 S to E 2 and were determined using non-linear regression analysis.
  • TABLE 5 IC 50 , 1 ⁇ 10 ⁇ 6 mol/l T-47D MCF-7 NGMN 0.0127 0.178 MPA 2.15 26.1

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US10206932B2 (en) 2014-05-22 2019-02-19 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10258630B2 (en) 2014-10-22 2019-04-16 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
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US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471148B2 (en) 2012-06-18 2019-11-12 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations

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JP2005519964A (ja) 2005-07-07
CN1652799A (zh) 2005-08-10
EP1482949A1 (fr) 2004-12-08
WO2003077927A1 (fr) 2003-09-25
CA2478165A1 (fr) 2003-09-25

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